1434
P. Stanetty et al.
LETTER
(4) Vaitekunas, A.; Nord, F. F. J. Am. Chem. Soc. 1953, 75,
Iodine was introduced with good yields utilizing elemen-
tal iodine (6f). Both reactions with benzaldehyde and cy-
clohexanone generated the corresponding alcohols 6b/i in
good yields. Carbonyl functionalities were introduced by
conversion with DMF and dry ice to the respective alde-
hyde 6g and carboxylic acid 6h. Transmetalation to silyl-
compound 6c opens several options to generate metal
species for subsequent transformations.
1764.
(5) (a) Moses, P.; Gronowitz, S. Ark. Kemi 1961, 18, 119.
(b) Gronowitz, S. Adv. Heterocycl. Chem. 1963, 1, 75.
(c) Gronowitz, S.; Holm, B. Acta Chem. Scand. 1969, 23,
2207. (d) Reinecke, M. G.; Adickes, H. W. J. Am. Chem.
Soc. 1968, 90, 511. (e) Reinecke, M. G.; Adickes, H. W.;
Pyun, C. J. Org. Chem. 1971, 36, 2690. (f) Reinecke, M.
G.; Adickes, H. W.; Pyun, C. J. Org. Chem. 1971, 36, 3820.
(g) Lukevics, E.; Arsenyan, P.; Belyakov, S.; Popelis, J.;
Pudova, O. Tetrahedron Lett. 2001, 41, 2039. (h) Fröhlich,
J. Bull. Soc. Chim. Belg. 1996, 105, 615. (i) Fröhlich, J.;
Hametner, C.; Kalt, W. Monatsh. Chem. 1996, 127, 325.
(j) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S.
Heterocycles 1983, 20, 2035.
(6) Reinecke, M. G.; Hollingworth, T. A. J. Org. Chem. 1972,
37, 4257.
(7) Fröhlich, J. In Progress in Heterocyclic Chemistry, Vol. 6;
Suschitzky, H.; Scriven, E. F. V., Eds.; Pergamon: New
York, 1994, 1–35.
(8) de Bie, D. A.; van der Plas, H. C. Tetrahedron Lett. 1968,
3905.
(9) de Bie, D. A.; van der Plas, H. C. Recl. Trav. Chim. Pays-Bas
1969, 88, 1246.
Table 1 Scope of the Methodology14
Electrophile
E
Product
Yield (%)
Water
H
6a
60
7815
68
68
30
11
76
Benzaldehyde
Trimethylsilylchloride
Hexachloroethane
Bromine
PhCH(OH) 6b
TMS
Cl
6c
6d
6e
6e
6e
Br
1,2-Dibromoethane
Br
(10) de Bie, D. A.; van der Plas, H. C.; Geurtsen, G.; Nijdam, K.
Recl. Trav. Chim. Pays-Bas 1973, 92, 245.
1,2-Dibromo-1,1,2,2-
tetrachloroethane
Br
(11) (a) Mallet, M.; Queguiner, G. Tetrahedron 1979, 35, 1625.
(b) Mallet, M.; Queguiner, J. G. Tetrahedron 1982, 38,
3035. (c) Cochenec, C.; Rocca, P.; Marsais, F.; Godard, A.;
Queguiner, G. Synthesis 1995, 321. (d) Sammakia, T.;
Stangeland, E. L.; Whitcomb, M. C. Org. Lett. 2002, 4,
2385. (e) Saitton, S.; Kihlberg, J.; Luthman, K. Tetrahedron
2004, 60, 6113.
(12) (a) Hertog, H. J.; Buurman, D. J. Recl. Trav. Chim. Pays-Bas
1973, 92, 304. (b) Arzel, E.; Rocca, P.; Marsais, F.; Godard,
A.; Queguiner, G. Tetrahedron Lett. 1998, 39, 6465.
(c) Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.; Queguiner,
G. Heterocycles 1999, 50, 215. (d) Arzel, E.; Rocca, P.;
Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron 1999,
50, 12149.
Iodine
I
6f
66
58
63
69
Dimethylformamide
CO2
CHO
COOH
C6H10OH
6g
6h
6i
Cyclohexanone
In conclusion we have developed a simple method to gen-
erate 4-bromo-2-phenyloxazole (6a) via a halogen dance
reaction starting from the easily available 5-bromo iso-
mer. Upon quenching of key intermediate 5 with various
electrophiles, a series of 5-substituted derivatives was
synthesized in good yields. This method opens also a new
pathway for the synthesis of 2,4,5-trisubstituted oxazoles.
Such applications by subsequent lithiation chemistry and
various cross-coupling reactions are currently under in-
vestigation in our laboratories.
(13) (a) Stangeland, E. L.; Sammakia, T. J. Org. Chem. 2004, 69,
2381. (b) Stanetty, P.; Schnürch, M.; Mereiter, K.;
Mihovilovic, M. D. J. Org. Chem. 2005, 70, 567.
(14) General Procedure for the Halogen Dance Reaction: A
freshly prepared solution of LDA (1.5 equiv) in anhyd THF
(10 mL) was added to a solution of 5-bromo-2-
phenyloxazole (1; 1 equiv) in anhyd THF at –80 °C under
nitrogen. The reaction was monitored by TLC, once the
reaction had reached completion (after 15–30 min,) the
corresponding electrophile (1.5 equiv in 5 mL anhyd THF)
was added and the reaction was allowed to warm to 0 °C
over 1 h. Water was added to this solution and 2/3 of the THF
was removed under reduced pressure. The mixture was
extracted with CH2Cl2 and washed with sat. NaHCO3 and
brine. The organic layer was dried over Na2SO4, filtered and
the solvent was removed under reduced pressure. The crude
product was purified by column chromatography.
(15) (4-Bromo-2-phenyloxazol-5-yl)phenylmethanol (6b):
Beige crystals (78%); mp 116–119 °C; 1H NMR (CDCl3):
d = 3.15 (br s, 1 H, OH), 6.00 (s, 1 H, CH), 7.20–7.56 (m, 8
Acknowledgment
We thank Syngenta Crop Protection, Basel, and Vienna University
of Technology for financial contributions to this project.
References
(1) (a) Mann, E.; Kessler, H. Org. Lett. 2003, 5, 4567. (b) You,
X.-L.; Kelly, J. W. J. Org. Chem. 2003, 68, 9506.
(c) Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.;
Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S. A.
Angew. Chem. Int. Ed. 2003, 42, 1753.
(2) (a) Hodgetts, K. J.; Kershaw, M. J. Org. Lett. 2002, 4, 2905.
(b) Iso, Y.; Shindo, H.; Hamana, H. Tetrahedron 2000, 56,
5353.
H, H3¢, H4¢, H5¢, 5H¢¢), 7.84–7.99 (m, 2 H, H2¢, H6¢); 13
C
NMR (CDCl3): d = 67.0 (d, CHOH), 114.7 (s, C4), 126.2 (d,
CH), 126.3 (s, C1¢), 126.5 (d, CH), 128.4 (d, C4¢), 128.5 (d,
CH), 128.5 (d, CH), 131.1 (d, C4¢¢), 139.4 (s, C1¢¢), 148.3 (s,
C5), 161.4 (s, C2).
(3) Kashima, C.; Arao, H. Synthesis 1998, 873.
Synlett 2005, No. 9, 1433–1434 © Thieme Stuttgart · New York